ABCMdb

PMID: 22661473

Burke TR, Fishman GA, Zernant J, Schubert C, Tsang SH, Smith RT, Ayyagari R, Koenekoop RK, Umfress A, Ciccarelli ML, Baldi A, Iannaccone A, Cremers FP, Klaver CC, Allikmets R
Retinal phenotypes in patients homozygous for the G1961E mutation in the ABCA4 gene.
Invest Ophthalmol Vis Sci. 2012 Jul 3;53(8):4458-67. doi: 10.1167/iovs.11-9166. Print 2012 Jul., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCA4 p.Gly1961Glu Genetics Retinal Phenotypes in Patients Homozygous for the G1961E Mutation in the ABCA4 Gene Tomas R. Burke,1, * Gerald A. Fishman,2 Jana Zernant,1 Carl Schubert,1 Stephen H. Tsang,1,3 R. Theodore Smith,1,4 Radha Ayyagari,5 Robert K. Koenekoop,6 Allison Umfress,7,† Maria Laura Ciccarelli,8 Alfonso Baldi,9 Alessandro Iannaccone,7 Frans P. M. Cremers,10 Caroline C. W. Klaver,11,12 and Rando Allikmets1,3 PURPOSE. Login to comment 1 ABCA4 p.Gly1961Glu We evaluated the pathogenicity of the G1961E mutation in the ABCA4 gene, and present the range of retinal phenotypes associated with this mutation in homozygosity in a patient cohort with ABCA4-associated phenotypes. Login to comment 2 ABCA4 p.Gly1961Glu We evaluated the pathogenicity of the G1961E mutation in the ABCA4 gene, and present the range of retinal phenotypes associated with this mutation in homozygosity in a patient cohort with ABCA4-associated phenotypes. Login to comment 4 ABCA4 p.Gly1961Glu Only patients homozygous for the G1961E mutation were enrolled. Login to comment 5 ABCA4 p.Gly1961Glu Only patients homozygous for the G1961E mutation were enrolled. Login to comment 9 ABCA4 p.Gly1961Glu We evaluated 12 patients homozygous for the G1961E mutation. Login to comment 10 ABCA4 p.Gly1961Glu We evaluated 12 patients homozygous for the G1961E mutation. Login to comment 14 ABCA4 p.Gly1961Glu Homozygous G1961E mutation in ABCA4 results in a range of retinal pathology. Login to comment 15 ABCA4 p.Gly1961Glu Homozygous G1961E mutation in ABCA4 results in a range of retinal pathology. Login to comment 28 ABCA4 p.Gly1961Glu The missense mutation G1961E occurs in exon 42 of the ABCA4 gene. Login to comment 29 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu The missense mutation G1961E occurs in exon 42 of the ABCA4 gene. Login to comment 30 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu While this has been characterized as the most common ABCA4 mutation, its frequency in the general population varies widely across ethnic groups, from approximately 0.2% in populations of European origin,18,19 to approximately 10% in East African (e.g., Somali) populations.20 It is considered a pathologic mutation for three main reasons: (1) it always co-segregates with the disease in families,21 (2) other mutations are found rarely in cis (i.e., on the same chromosome), and (3) it affects protein function as determined by indirect functional tests (ATP-ase activity and ATP binding).22 The heterozygous G1961E mutation, in combination with a different ABCA4 allele on the other chromosome, has been associated with a localized disease process that is confined to the posterior pole, normal full-field electroretinogram (ffERG), absence of the ''dark choroid`` sign on fluorescein angiography (FA), and BEM on fundus autofluorescence (FAF).19,23-25 Despite all these data, there still is debate as to whether this mutation causes retinal pathology in homozygosity. Login to comment 31 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu We studied patients homozygous for the G1961E allele to demonstrate the pathogenicity of the mutation in homozygosity and to describe further the variation in retinal phenotypes associated with it. Login to comment 32 ABCA4 p.Gly1961Glu MATERIALS AND METHODS Patients Only patients who demonstrated phenotypes consistent with ABCA4 disease (i.e., BEM, STGD1, CRD, or RP) and who were homozygous for the G1961E mutation in the ABCA4 gene were included. Login to comment 46 ABCA4 p.Gly1961Glu In our study, however, we examined the full range of retinal phenotypes in a cohort of patients homozygous for the G1961E mutation to demonstrate the pathogenicity of this mutation in homozygous state. Login to comment 47 ABCA4 p.Gly1961Glu In our study, however, we examined the full range of retinal phenotypes in a cohort of patients homozygous for the G1961E mutation to demonstrate the pathogenicity of this mutation in homozygous state. Login to comment 82 ABCA4 p.Gly1961Glu All patients were homozygous for the G1961E mutation in the ABCA4 gene. Login to comment 83 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Asn96Lys All patients were homozygous for the G1961E mutation in the ABCA4 gene. Login to comment 84 ABCA4 p.Gly1961Glu ABCA4 p.Asn96Lys ABCA4 p.Asn96Lys Patient 9 was double homozygous for the N96K mutation together with G1961E. Login to comment 85 ABCA4 p.Asn96Lys For patients 8-1 and 8-2, N96K was detected on only one allele in each patient. Login to comment 86 ABCA4 p.Gly1961Glu ABCA4 p.His1838Asp Two other siblings (patients 7-1 and 7-2), who belonged to a consanguineous Jordanian family, also had the H1838D mutation detected in homozygosity, in addition to being homozygous for the G1961E mutation. Login to comment 87 ABCA4 p.Gly1961Glu ABCA4 p.His1838Asp Two other siblings (patients 7-1 and 7-2), who belonged to a consanguineous Jordanian family, also had the H1838D mutation detected in homozygosity, in addition to being homozygous for the G1961E mutation. Login to comment 88 ABCA4 p.Thr1253Met Patient 3 had an additional heterozygous T1253M variant. Login to comment 89 ABCA4 p.Thr1253Met Patient 3 had an additional heterozygous T1253M variant. Login to comment 90 ABCA4 p.Gly1961Glu ABCA4 p.Asn96Lys ABCA4 p.Asn96Lys ABCA4 p.Asn96Lys ABCA4 p.His1838Asp ABCA4 p.His1838Asp ABCA4 p.Thr1253Met Summary of Demographic, Clinical, and Functional Data in Patients Homozygous for the G1961E Mutation Patient #, Sex Additional ABCA4 Mutations Onset Age (years) Age at Exam (years) Duration (years) VA Clinical Phenotype ERG Group Silent Choroid Type of Perimetry Scotoma Location OD OS Milder Phenotypes 1, M 19 34 15 20/150 20/100 I I ND MP-1 Central 2, F 20 21 1 20/25 20/40 I I Absent ND ND 3, M T1253M 32 46 14 20/25 20/40 I I Absent GVF Perifoveal 4, F 43 67 24 20/40 20/150 II I ND MP-1 Central 5, F 48 65 17 20/150 20/200 I I ND MP-1 Central 6, F 64 86 22 20/200 20/200 II I Absent GVF Central Severe Phenotypes 7-1, M H1838D (Hom) 4 12 8 20/250 20/250 III III ND GVF Central 7-2, F H1838D (Hom) 7 13 6 20/200 20/200 IV III Peripapillary Ring GVF Central 8-1, F N96K 7 46 39 20/2000 20/2000 III III Peripapillary Ring GVF Central 8-2, M N96K 10 49 39 20/400 20/400 IV ND ND GVF Central 9, F N96K (Hom) 12 59 47 10/400 10/400 IV III ND ND ND 10, M 20 51 31 20/25 20/25 III RP ND GVF Perifoveal Each number identifies distinct families. Login to comment 91 ABCA4 p.Gly1961Glu ABCA4 p.Asn96Lys ABCA4 p.Asn96Lys ABCA4 p.Asn96Lys ABCA4 p.His1838Asp ABCA4 p.His1838Asp ABCA4 p.Thr1253Met Summary of Demographic, Clinical, and Functional Data in Patients Homozygous for the G1961E Mutation Patient #, Sex Additional ABCA4 Mutations Onset Age (years) Age at Exam (years) Duration (years) VA Clinical Phenotype ERG Group Silent Choroid Type of Perimetry Scotoma Location OD OS Milder Phenotypes 1, M 19 34 15 20/150 20/100 I I ND MP-1 Central 2, F 20 21 1 20/25 20/40 I I Absent ND ND 3, M T1253M 32 46 14 20/25 20/40 I I Absent GVF Perifoveal 4, F 43 67 24 20/40 20/150 II I ND MP-1 Central 5, F 48 65 17 20/150 20/200 I I ND MP-1 Central 6, F 64 86 22 20/200 20/200 II I Absent GVF Central Severe Phenotypes 7-1, M H1838D (Hom) 4 12 8 20/250 20/250 III III ND GVF Central 7-2, F H1838D (Hom) 7 13 6 20/200 20/200 IV III Peripapillary Ring GVF Central 8-1, F N96K 7 46 39 20/2000 20/2000 III III Peripapillary Ring GVF Central 8-2, M N96K 10 49 39 20/400 20/400 IV ND ND GVF Central 9, F N96K (Hom) 12 59 47 10/400 10/400 IV III ND ND ND 10, M 20 51 31 20/25 20/25 III RP ND GVF Perifoveal Each number identifies distinct families. Login to comment 95 ABCA4 p.Gly1961Glu The phase and true homozygosity of the G1961E mutation were determined by segregation analyses. Login to comment 96 ABCA4 p.Gly1961Glu The phase and true homozygosity of the G1961E mutation were determined by segregation analyses. Login to comment 105 ABCA4 p.Gly1961Glu ABCA4 p.Thr1253Met Only one patient in this group (patient 3) had a heterozygous T1253M variant detected in the ABCA4 gene, in addition to the homozygous G1961E mutation. Login to comment 106 ABCA4 p.Gly1961Glu ABCA4 p.Thr1253Met Only one patient in this group (patient 3) had a heterozygous T1253M variant detected in the ABCA4 gene, in addition to the homozygous G1961E mutation. Login to comment 132 ABCA4 p.Gly1961Glu Interestingly, 5 of 6 patients in this group, with the exception of patient 10, harbored heterozygous or homozygous ABCA4 variants in addition to G1961E. Login to comment 133 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu Interestingly, 5 of 6 patients in this group, with the exception of patient 10, harbored heterozygous or homozygous ABCA4 variants in addition to G1961E. Login to comment 134 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu DISCUSSION We illustrated the phenotypic expression of retinal disease associated with homozygous G1961E mutation in the ABCA4 gene. Login to comment 135 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu It was suggested previously that G1961E was not pathogenic, at least in homozygosity, for two reasons. Login to comment 136 ABCA4 p.Gly1961Glu First, the mutation is detected at approximately 10% frequency in the general population from Somalia, predicting that 1/100 Somalis are homozygous for G1961E.20 Since, as stated in that FIGURE 2. Login to comment 146 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu study, ''Stargardt disease is not known to be 100 times more prevalent in Somalia than in the United States, it suggests that G1961E does not frequently cause disease in the homozygous state.`` Secondly, The same group presented an asymptomatic 25-year-old Somali man homozygous for G1961E (Shankar SP. IOVS 2006;47:ARVO E-Abstract 1699). Login to comment 147 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu study, ''Stargardt disease is not known to be 100 times more prevalent in Somalia than in the United States, it suggests that G1961E does not frequently cause disease in the homozygous state.`` Secondly, The same group presented an asymptomatic 25-year-old Somali man homozygous for G1961E (Shankar SP. IOVS 2006;47:ARVO E-Abstract 1699). Login to comment 148 ABCA4 p.Gly1961Glu It is true that the G1961E mutation is frequent in East Africa. Login to comment 149 ABCA4 p.Gly1961Glu It is true that the G1961E mutation is frequent in East Africa. Login to comment 151 ABCA4 p.Gly1961Glu One possibility is that the G1961E mutation is pathogenic in Europeans and not in East Africa, that is the change happened twice or multiple times. Login to comment 152 ABCA4 p.Gly1961Glu One possibility is that the G1961E mutation is pathogenic in Europeans and not in East Africa, that is the change happened twice or multiple times. Login to comment 153 ABCA4 p.Gly1961Glu In addition, in our study 50% (3 of 6) of patients with homozygous G1961E and no additional ABCA4 variants had a late disease onset, over 25 years of age. Login to comment 154 ABCA4 p.Gly1961Glu In addition, in our study 50% (3 of 6) of patients with homozygous G1961E and no additional ABCA4 variants had a late disease onset, over 25 years of age. Login to comment 156 ABCA4 p.Gly1961Glu Large studies in elderly subjects of East African descent could reveal the correlation between the homozygous G1961E mutation and eye disease in those populations. Login to comment 157 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu Large studies in elderly subjects of East African descent could reveal the correlation between the homozygous G1961E mutation and eye disease in those populations. Login to comment 158 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu In other populations, for example those of European descent, a normal visual function and a normal clinical examination do not exclude ABCA4 disease, especially when caused by the G1961E mutation in homozygosity. Login to comment 159 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu A likely scenario has the G1961E mutation arising once, in East Africa, and then lost (eliminated by selective pressure) in other regions due to its pathogenicity and earlier onset in heterozygosity with other, more severe, ABCA4 alleles. Login to comment 160 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu It is possible that these alleles are rare in East Africa and the mild G1961E mutation itself does not result in the disease during reproductive age, and, therefore, is not under selective pressure. Login to comment 161 ABCA4 p.Gly1961Glu Another proof of pathogenicity for the homozygous G1961E comes from allele frequency calculations. Login to comment 165 ABCA4 p.Gly1961Glu We have detected 6 G1961E homozygotes after screening approximately 600 random STGD1 patients, which is the exact predicted frequency of homozygosity. Login to comment 166 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu We have detected 6 G1961E homozygotes after screening approximately 600 random STGD1 patients, which is the exact predicted frequency of homozygosity. Login to comment 167 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Thr1253Met Six patients had other ABCA4 variants on the same chromosome with G1961E. Login to comment 168 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Asn96Lys ABCA4 p.Thr1253Met One patient harbored a heterozygous T1253M variant, which previously has been reported sometimes to form a complex allele with G1961E.41 It is predicted to give rise to an amino acid change that lies outside the functional domain of the ABCA4 protein, it never occurs without G1961E, and, therefore, its pathogenicity has not been confirmed. Login to comment 169 ABCA4 p.Asn96Lys The N96K missense change, which previously has been reported as a disease causing mutation in the ABCA4 FIGURE 5. Login to comment 183 ABCA4 p.Gly1961Glu ABCA4 p.His1838Asp These genetic findings in our patients of Italian origin are in keeping with recent reports of this mutation in Italian populations with STGD1.43 The H1838D mutation has been reported previously in patient 7-1.31 This variant clearly has a profoundly deleterious effect on ABCA4 protein function, at least when present in conjunction with the G1961E in homozygosity, giving rise to a severe, early-onset and complex phenotype in both siblings from a consanguineous family of Jordanian descent. Login to comment 184 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.His1838Asp These genetic findings in our patients of Italian origin are in keeping with recent reports of this mutation in Italian populations with STGD1.43 The H1838D mutation has been reported previously in patient 7-1.31 This variant clearly has a profoundly deleterious effect on ABCA4 protein function, at least when present in conjunction with the G1961E in homozygosity, giving rise to a severe, early-onset and complex phenotype in both siblings from a consanguineous family of Jordanian descent. Login to comment 185 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu In general, patients homozygous for the G1961E mutation demonstrated a later onset of visual symptoms than typically would be seen in STGD1.27,44,45 However, despite the better prognosis for overall retinal function in these G1961E homozygous patients (as determined by normal ffERGs) the final visual acuity can still reach 20/200. Login to comment 186 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu Previous reports have focused mainly on the phenotypes of patients with G1961E in simple or compound heterozygosity. Login to comment 187 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu The majority of those patients revealed a milder retinal disease phenotype confined to the central macula, with absence of the dark choroid sign on FA, and with normal ffERG.24,25,46 This milder phenotype correlates with the observation that although there is a reduction in ATPase activity with the G1961E mutation, there is comparable yield to the levels seen in the wild-type.46 However, its basal ATPase activity appears inhibited rather than stimulated by retinal.22 While all other patients had a clinical diagnosis of STGD1 before genetic confirmation, patient 6 initially was diagnosed with dry AMD with GA, due to the late onset of disease and the absence of flecks on clinical examination. Login to comment 188 ABCA4 p.Gly1961Glu During investigation of the genetic causes of AMD the patient was screened for mutations in the ABCA4 gene and the homozygous G1961E mutation was detected, highlighting an important issue in crossover between AMD and ABCA4-associated disease phenotypes. Login to comment 190 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu In summary, our findings demonstrate the pathogenicity of the G1961E mutation by the phenotypic manifestation of STGD1 patients where only the G1961E mutation was detected in homozygosity. Login to comment 191 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu In summary, our findings demonstrate the pathogenicity of the G1961E mutation by the phenotypic manifestation of STGD1 patients where only the G1961E mutation was detected in homozygosity. Login to comment 192 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu As observed previously in patients compound heterozygous for the G1961E mutation, phenotypic expression was somewhat atypical for classical STGD1, with the traditional findings of retinal flecks and a dark choroid effect on FA largely absent in association with the G1961E mutation in homozygosity. Login to comment 193 ABCA4 p.Gly1961Glu Lastly, a normal visual acuity and a normal clinical examination should not exclude a diagnosis of ABCA4 disease, especially when the G1961E mutation is the putative genetic cause. Login to comment 194 ABCA4 p.Gly1961Glu Lastly, a normal visual acuity and a normal clinical examination should not exclude a diagnosis of ABCA4 disease, especially when the G1961E mutation is the putative genetic cause. Login to comment